The life cycle of malaria involves receptor-specific interactions that allow invasion of red cells and attachment of infected red cells to endothelium. These specific events are potential targets for vaccines and drug interventions. We have demonstrated that the same motif involved in invading red cells for P. vivax and P. falciparum is found as two to five copies on the variant antigen of P. falciparum. We are determining if these motifs are involved in adhesion to endothelium and to red cells to form rosettes, a pathogenic marker. One of the domains on the variant antigen binds to CD36 on endothelium. As most parasites bind CD36 and the major protective immune response is to these variant antigens, it may be possible to develop a vaccine against this domain on the parasite. Although this is counterintuitive (variation is designed to escape immunity), the epitopes around this domain may not normally induce immunity because they are cryptic, that is, not immunogenic during infection, but protection can be induced after vaccination. We are also searching for other receptors for invasion of red cells and attachment to endothelium.